My long-term career goal is to establish a productive basic science research group to understand the biology of viral pathogens and their infected hosts, ultimately translating the findings towards the development of strategies to treat or prevent viral diseases. The short-term career goal is to develop the essential expertise and skills to foster my transition from a postdoctoral trainee to an independent investigator. In the laboratory of Dr. Charles Wood as a PhD student, I conducted studies to decipher the mechanism of viral and cellular factors involved in Kaposi's sarcoma-associated herpesvirus (KSHV) lytic reactivation from latency. In the laboratory of Dr. Bernard Moss, I employed high-throughput next-generation sequencing technique and other approaches to investigate poxvirus gene expression and the host interaction in a genome-wide scale. These experiences allowed me to develop expertise necessary for my proposed studies. Environment: The NIH Intramural Research Program offers both strong well-established research programs and rich resources for career development of postdoctoral fellows. The NIAID Division of Intramural Research (DIR) conducts basic and clinical research in a broad range of disciplines related to allergy, immunology and infectious diseases. The Laboratory of Viral Diseases has seven nationally and internationally recognized principal investigators that carry out cutting edge research on poxvirus, HIV, influenza virus, herpesvirus, flavivirus and papilloma virus. The mentor, Dr. Bernard Moss is a prominent poxvirologist with significant contributions in nearly all aspects of poxvirus research and has trained many principal investigators in his career. I will take the advantages of the NIH and Dr. Moss's laboratory to enhance my intellectual background in immunology, develop expertise necessary for conducting the proposed study and improve my skills on scientific communication, manuscript- and grant-writing, lab management, job search and expand the scope of my research. Research: Poxviruses can cause deadly human and animal diseases, such as smallpox and monkeypox and have the potential to be used as biological weapons. They are also extensively used as expression vectors for vaccine development. Virus-host interaction during the host innate immune response plays a crucial role in shaping the outcome of viral infection. My previous work on the simultaneous profiling the transcriptomes of vaccinia virus (the prototype poxvirus) and its infected host has shown that a small group of cellular mRNAs was increased at the early time of vaccinia virus infection before viral DNA replication, suggesting specific host response to virus. The upregulated mRNAs are enriched for genes involved in the innate immune response, including inflammatory cytokines, particularly those in the IL-6 family. However, during the post DNA replication stage of vaccinia virus infection, vaccinia virus induced the downregulation of host mRNAs, termed host shutoff, including many genes involved in the innate immune response and those genes were upregulated at the early stage. The goal of this proposal is to understand the induction and shutoff of the host innate immune response during poxvirus infection with a specific focus on inflammatory response. I hypothesize that while vaccinia virus induces a rapid host innate immune response, particularly the inflammatory response, before viral DNA replication, the host shutoff during the post DNA replication stage provides a potent mechanism to blunt host antiviral innate immune responses. In Specific Aim 1, I will identify host antiviral innate immune genes induced by VACV infection and the mechanisms of IL-6 family cytokine induction in response to VACV infection. In Specific Aim 2, I will determine the effect of the host shutoff on the antiviral innate response to VACV infection. Finally, in Specific Aim 3, I will determine the role of IL-6 family cytokines and signaling during VACV replication. Completion of the study will advance the understanding of poxvirus-host interactions, and may ultimately lead to the development of safer and more effective poxvirus vectors and novel strategies to prevent poxvirus infection.